Microstructural white matter changes in carriers of the DYT1 gene mutation

Carbon, Maren; Kingsley, Peter B.; Su, Sherwin L.; Smith, Gwenn S.; Spetsieris, Phoebe; Bressman, Susan; Eidelberg, David

doi:10.1002/ana.20177

Cited by 129 publications

(55 citation statements)

References 20 publications

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“…Thus, dystonia is likely to be a disorder involving multiple brain regions. The lack of neuronal degeneration in torsion dystonia patients suggests the possibility of functional defects, possibly caused by subtle changes in connectivity such as those reported in sensorimotor cortex by diffusion tensor magnetic resonance imaging (Carbon et al, 2004). Though there is no evidence of neuronal degeneration, torsinA, laminA, and ubiquitin inclusions have been reported in midbrain of DYT1 patients (McNaught et al, 2004).…”

Section: Discussionmentioning

confidence: 94%

Developmental patterns of torsinA and torsinB expression

2006

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Early onset torsion dystonia is characterized by involuntary movements and distorted postures and is usually caused by a 3-bp (GAG) deletion in the DYT1 (TOR1A) gene. DYT1 codes for torsinA, a member of the AAA + family of proteins, implicated in membrane recycling and chaperone functions. A close relative, torsinB may be involved in similar cellular functions. We investigated torsinA and torsinB message and protein levels in the developing mouse brain. TorsinA expression was highest during prenatal and early postnatal development (until postnatal day 14; P14), whereas torsinB expression was highest during late postnatal periods (from P14 onwards) and in the adult. In addition, significant regional variation in the expression of the two torsins was seen within the developing brain. Thus, torsinA expression was highest in the cerebral cortex from embryonic day 15 (E15)-E17 and in the striatum from E17-P7, while torsinB was highest in the cerebral cortex between P7-P14 and in the striatum from P7-P30. TorsinA was also highly expressed in the thalamus from P0-P7 and in the cerebellum from P7-P14. Although functional significance of the patterns of torsinA and B expression in the developing brain remains to be established, our findings provide a basis for investigating the role of torsins in specific processes such as neurogenesis, neuronal migration, axon/dendrite development, and synaptogenesis.

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Section: Discussionmentioning

confidence: 94%

Developmental patterns of torsinA and torsinB expression

2006

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“…Indeed, these metabolic changes are present during sleep when no involuntary movements are present, suggesting an association with genotype rather than phenotype (8,10,11). Magnetic resonance DTI shows white matter abnormalities in dystonia gene carriers (12,13), and tractographic analysis of these abnormalities has associated these changes with reduced integrity of cerebellothalamocortical (CbTC) motor pathways (6), which modulate the excitability and synaptic plasticity of the sensorimotor cortex (14). Irrespective of clinical penetrance, DYT1 carriers exhibited reduced connectivity in the proximal cerebellothalamic segment of this pathway.…”

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confidence: 99%

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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114

112

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The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent micro-PET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.connectivity | regional metabolism | brain networks I n recent years, advanced imaging technologies such as PET and magnetic resonance diffusion tensor imaging (DTI) have provided unique information regarding the impact of specific genetic mutations on brain structure and function. However, to control for variability in genetic background and additional confounders such as age and sex, many more mutation carriers (and control subjects) are required than can conveniently be scanned, even in a multicenter design. Human imaging studies may also suffer from relatively low spatial resolution and sensitivity. These considerations motivated the current study in which high field magnetic resonance DTI was performed ex vivo in an experimental genetic model of a brain disorder.Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2). DYT1 dystonia, the most common inherited form of the disease, is caused by a dominantly inherited 3-bp in-frame deletion in the TOR1A gene that removes a single glutamic acid (ΔE) from the torsinA protein (3). This lowprevalence mutation (approximately 1 in 30,000...

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“…DTI tractography is interesting in primary dystonia because this neurodevelopment disorder might disrupt cortico-striatal and/or cerebello-thalamic pathways. Indeed, abnormalities have been reported in the cortex (138)(139)(140), basal ganglia (141,142), internal capsule (143), or thalamocortical pathways (144).…”

Section: Neuronal Network (Imaging Data)mentioning

confidence: 99%

Dystonia Pathophysiology: A Critical Review

Burbaud¹

2012

Dystonia - The Many Facets

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Microstructural white matter changes in carriers of the DYT1 gene mutation

Cited by 129 publications

References 20 publications

Developmental patterns of torsinA and torsinB expression

Developmental patterns of torsinA and torsinB expression

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Dystonia Pathophysiology: A Critical Review

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